A primary focus of my translational research program is the delineation of epigenetic mechanisms dysregulating gene expression in thoracic malignancies, and the development of novel and effective pharmacologic regimens targeting the epigenome in these neoplasms. Our published studies pertaining to more than 100 patients with lung and esophageal cancers and pleural mesotheliomas, or pulmonary metastases from non-thoracic malignancies have clearly demonstrated that DNA demethylating agents (Decitabine; DAC), and HDAC inhibitors, such as romidepsin (DP) alone or in combination with other investigational agents can modulate gene expression in thoracic malignancies and induce immune responses against these neoplasms. Although no objective clinical regressions have been observed, prolonged stabilization of disease has been noted in approximately 10% of patients. Our goal has always been to couple epigenetic priming regimens with immunotherapy for thoracic malignancies. Presently, poor biodistribution and systemic toxicities prevent optimal, chronic administration of epigenetic agents in patients with solid tumors. For example, DNA demethylating agents such as DAC and azacytidine (AZA) have very limited bioavailability when administered alone as oral agents, and extremely short half-lives (5min) resulting in poor uptake into solid tumors due to cytidine deaminase (CDA) which is present at high levels throughout the body. Recent studies in non-human primates and a clinical trial in patients with sickle cell disease, have demonstrated that an oral formulation of tetrahydrouridine (THU) can markedly increase Cmax (50nM) and T1/2 (4 hours) of oral DAC, thereby facilitating systemic DNA demethylation. These findings provided the rationale for a phase II trial evaluation oral DAC/THU and the immune checkpoint inhibitor nivolumab as second line therapy for patients with NSCLC; this trial was conducted at the NCI (PI: DSS) and the Cleveland Clinic. Impressive responses were observed in several patients who received the oral epigenetic priming regimen; in the absence of oral DAC/THU, these patients would not have been expected to respond to immune checkpoint blockade. This trial has recently completed accrual, and a manuscript pertaining to our results will be submitted for publication in the near future. Additionally, a phase I/II study of oral DAC/THU and pembrolizumab as first line therapy for patients with inoperable NSCLC has been initiated. Thus far, two of 4 evaluable patients responded to therapy; one of whom had a near-CR. This trial has recently been amended to enable evaluation of esophageal cancer patients. The rationale for and results of these epigenetic-immunotherapy efforts were presented in large cancer immunotherapy symposia at ASCO in 2018 and 2019. To further optimize epigenetic priming of pulmonary malignancies for immune checkpoint blockade while decreasing potential systemic toxicities, we have recently initiated a phase I/II trial to examine the toxicities and potential efficacy of AZA administered via inhalation techniques in combination with M7824, a dual immune checkpoint inhibitor-TGF-beta trap in patients with locally advanced lung cancers or pulmonary metastases. No similar efforts are currently underway elsewhere in the world, and this trial is intended to establish the paradigm for evaluation of a series of diverse aerosolized epigenetic agents alone or in combination with adoptive immunotherapy for the treatment of locally advanced pulmonary malignancies.